Circulating tumor-DNA for the proper allocation of completion resection in early colorectal cancer
After the introduction of the nationwide screening programme for colorectal cancer (CRC) in Denmark, the number of early CRC cases have increased. Early CRC is here defined as pathological T1 category (pT1). Many of these early tumors are removed locally, either during colonoscopy, where simple polypectomy or endoscopic mucosal resection (EMR) is performed, or through planned transanal minimally invasive surgery (TAMIS) in clinical T1 (cT1) rectal cancer.
This early detection of cancer and thereby an improved prognosis, is in itself very positive, but have also created new clinical dilemmas. In the case of locally resected pT1 CRC in particular, due to the small, but not always insignificant, risk of lymph node metastasis, one important question emerges: Is the patient cured by local resection alone? – or is segmental bowel resection (termed completion resection) required in order to achieve resection of regional, potential metastatic, lymph nodes?
Whether completion resection is recommended at the Multi-Disciplinary Team (MDT) board meeting is based on the radicality of the local excision as well as the presence of certain histopathological criteria assessed in the locally removed specimen.
The presence of these criteria does not, however translate directly into the presence of lymph node metastasis – merely into a theoretical increased risk of same. Thus, the current practice is based on evidence biased of methodological considerations and from a previous era and does not accurately stratify patients into those with residual disease, and those without. After completion bowel resection for all pT1 CRC cases in Denmark, the fraction of cases with metastatic lymph nodes has been around 15% for many years. In effect, in the remaining 85% of cases, local tumor removal alone would presumably be curative – and the surgical resection presumably constitutes overtreatment.
In the years 2016 through 2018, 382 colonic and 120 rectal resections were performed as completion resections in Denmark, which correspond to 130 and 40 resections/year, respectively.
The investigation of blood samples for the presence of circulating tumor-DNA (ctDNA) is a new and promising method for cancer detection. The method utilizes the fact that cancer cells release ctDNA to the blood, and that this ctDNA has a half-life of only two hours. In theory, ctDNA detected in blood drawn from a patient a few days after local excision of a tumor, indicate that residual disease is present and further treatment, such as completion resection, is needed.
ctDNA has not previously been used as a method to stratify patients according the risk of residual disease, after local removal of early CRC.
The purpose of this study is to investigate, whether analyses of ctDNA can correctly identify patients with residual disease after local removal of early (pT1) CRC. If this identification proves to be accurate, many patients can be spared of completion bowel resection.
This is a prospective, strictly observational pilot study, assessing the association between preoperative ctDNA analyses and the presence of residual disease established by pathological evaluation of the resected specimen following completion resection.
Patients having undergone local resection of pT1 colorectal cancer and with planned completion resection, as recommended by the local MDT board
- Patients not able to understand information about the study and/or give informed consent
- Patients not accepting blood samples stored in biobank
- Cases with non-obtainable primary tumor tissue, required for the conduction of mutational analyses
- Other recent (within 5 years) or current malignant disease, except basocellulary carcinoma of the skin
- Planned completion resection due to other factors, such as patient’s wish or hereditary disposition for CRC, and with the absence of risk factors mentioned above
Correct allocation of patients, using ctDNA analyses, into the two groups: Residual disease present or residual disease not present, with standard pathology evaluation as gold standard.
Significance & Perspectives
ctDNA has not previously been used for the detection of residual disease after local resection of early colorectal cancers. Hence, this study will be the first of its kind, utilizing a newly established, highly sensitive analysis method for the detection of microscopic levels of ctDNA.
With the large, and still increasing, number of yearly patients, whom may benefit from a more accurate risk stratification and thereby be spared of surgery, the impact of this study will be significant and may be one more step towards personalized medicine in cancer treatment.
Finally, the current study will form the basis of the design of a subsequent randomized controlled trial, where the ctDNA analyses are used to actively decide, whether completion resection is justified or not.